This invention relates to a method for the treatment of withdrawal symptoms associated with smoking cessation with preparations containing nicotine and such preparations.
Nicotine is the major alkaloid of tobacco and is the most potent alkaloid in tobacco smoke.
There is now strong evidence for regarding smoking as a form of drug dependence, the drug, of course, being nicotine. Measurements of the concentrations of nicotine, and its metabolite cotinine, in the blood of smokers have demonstrated the extent to which smoking is a drug taking activity. Rapid absorption through the lungs enables the smoker to get an intravenous-like shot of nicotine after each inhaled puff. By varying puff rate, puff volume and depth of inhalation, smokers regulate their nicotine intake and have literally finger-tip control over the concentrations of nicotine delivered to their brain. Nicotine has been shown to act as a primary reinforcer in animals and many of its pharmacological effects are potentially rewarding. It includes tolerances and smokers suffer from physical as well as subjective effects when it is withdrawn.
Nicotine induces changes in the number of nicotinic cholinergic receptors and this is one possible mechanism underlying tolerance. Besides its main direct action at nicotinic cholinergic receptor sites, through linkage of these sites with other neurotransmitter systems, nicotine has indirect effects on the release of most of the known neurotransmitters. Through its action on the locus coeruleus it has a widespread effect on noradrenergic activity throughout the brain. It also activates ascending dopaminergic pathways thought to be involved with the brainstem and hypothalamic reward systems. Its effect on dopaminergic activity may link in with the lower incidence of Parkinson's Disease among cigarette smokers. Nicotine also stimulates cholinergic neurones in the nucleus basalis of Meynert which in turn project to all regions of the cortex. This and similar actions on nerve cells in the septum, which project to the hippocampus, may be involved in the effect of nicotine on memory processes and suggest that nicotine may be of potential value in enhancing performance in people with early Alzheimer's Disease. Nicotine also influences serotonergic systems.
By smoking a cigarette, the smoker receives an initial burst of nicotine into the bloodstream, which then rapidly declines. The urge to smoke increases as the nicotine level continues to fall below a given point in the blood level, a point which can vary with each smoker. However, it has been shown that the normal plasma trough level associated with usual smoking is approximately 5-15 ng/ml within one hour of first smoking. At the time of smoking the plasma level is between 15 ng/ml and 30 ng/ml and the natural urge to smoke is thereby suppressed. When nicotine levels fall to a level of 15 ng/ml or less, nicotine intake is required to suppress the smoking urge. Thus the objective for any smoking cessation therapy involving nicotine administration would be the rapid attainment and maintenance of such plasma levels.
One of the approaches currently used in smoking cessation therapy using nicotine is that employed by a nicotine containing chewing gum sold under the Trade Mark NICORETTE. This gum contains a cation exchange resin containing 2 or 4 mg of nicotine. The release rate of nicotine from this gum is dependent upon the duration and vigour of chewing. There can be a considerable variation in absorption of nicotine from gum depending upon how a person chews the gum. To achieve adequate absorption of nicotine vigorous chewing is required. It has been reported that normal chewing results in over 90% of nicotine being released within 20 minutes. Thus the system requires frequent administration by the smoker in an attempt to maintain effective plasma levels and thus curb the urge to smoke. The plasma levels achieved by the 2 mg gum fail to achieve the levels measured after cigarette smoking and, therefore, the 4 mg gum would be required by the smoker in most cases.
Because buccal absorption is pH dependent, a buffer has been incorporated into the gum in an attempt to maintain the buccal environment at constant pH. While it is intended that this buffer maintain the pH in the mouth at approximately 8.5, there is no experimental data in the literature to support this conclusion. Such pH control is of considerable importance in relation to both the extent and variability of absorption of nicotine into the bloodstream from this site of administration.
Another feature of such oral nicotine administration is the susceptibility of the patient to gastrointestinal upsets. Also the poor taste qualities associated with oral nicotine administration makes such a method of smoking cessation unpopular with the patient and thus can lead to poor compliance, even to the level of resumption of cigarette smoking.
A major problem in maintaining continuous effective therapeutic levels of nicotine in the bloodstream with the nicotine gum is the inability to self-administer during the time the patient is asleep, thus leading to low or even zero levels of nicotine in the morning and a return of the smoking urge. Even with immediate administration of the nicotine gum, it can take up to one hour before effective plasma levels of nicotine are again attained.
Additionally, the mode of administration of the gum, in that it involves frequent dosage and chewing, is a practice which is widely regarded as being socially unacceptable. Generally, gum will have to be chewed at the same frequency as the person's smoking pattern and usually every hour to achieve adequate plasma levels of nicotine. With gum there is no assistance in breaking the smoking habit.
Another aspect of oral nicotine administration in the gum form, is that there is now a suggestion of the chance of contracting cancer of the mouth and throat, as a result of frequent chewing of resin based nicotine containing gum. Mouth ulcers have also been observed in persons chewing nicotine gum.
Another development has been the introduction of low-nicotine cigarettes. However, again with such low-nicotine cigarettes there is no breaking of the smoking habit.
In a study by Jed E. Rose et al reported in Clin. Pharmacol. Ther. October 1985 a 30% aqueous solution of nicotine base was applied to intact skin under an opaque polyethylene patch. The purpose of the patch was to prevent subjects observing any changes in skin colour such as redness. With such a solution immediate release of nicotine was observed. However, painting on of a nicotine solution as described by Jed E. Rose et al would not be socially acceptable.
Nicotine is known to show a high degree of absorption by the percutaneous route. A method for the percutaneous or transdermal administration of nicotine is known from U.S. Pat. No. 4,597,961. However, nicotine has not heretofore been used commercially by the percutaneous or transdermal route in a method of smoking cessation therapy. Various devices for the percutaneous or transdermal administration of nicotine are disclosed in U.S. Pat. No. 4,597,961. However, these are clearly not commercial devices. U.S. Pat. No. 4,597,961 refers to a dose range of nicotine of 15 to 25 ng/l or 15 to 25 picograms/ml. However, as indicated above trough plasma levels of nicotine are in the range 5-15 ng/ml and levels at the time of smoking rise to 15-30 ng/ml.
The transcutaneous devices disclosed in U.S. Pat. No. 4,597,961 have substantial thickness viz 2 cm and hence are rather bulky. It is stated the onset of nicotine activity is in the range of 1-2 minutes with a duration of action of from 30-45 minutes. Hence, the device would have to be frequently applied, for example, hourly and even then it is doubtful whether adequate levels of nicotine would be achieved having regard to the specified dosage of 15 to 25 ng/l.